Intense exercise and food restriction cause similar hypothalamic neuropeptide Y increases in rats.

Neuropeptide Y (NPY) is a potent central appetite stimulant whose concentrations rise markedly in hypothalamic appetite-regulating regions in food-deprived rats. To determine whether increased energy expenditure also affects hypothalamic NPY, we studied the effects of intense physical exercise in rats (n = 10) running voluntarily on a large-diameter exercise wheel. Running was initiated by restricting food intake but stabilized at an average of 8 km/day when food intake was matched to that in 11 nonexercised, freely fed controls [23.9 +/- 1.9 (SE) g/day vs. 24.7 +/- 1.3 g/day; P > 0.5]. Running expended approximately 40% of daily energy intake, and weight gain was significantly inhibited. A separate group (n = 10) of nonexercised rats was food restricted (approximately 15 g/day) to match the weights of the exercised rats. The rats were killed after 40 days, when both experimental groups weighed 30% less than controls (P < 0.01). Hypothalamic NPY concentrations showed significant (P < 0.01) increases of 30-70% in specific regions (arcuate and dorsomedial nuclei and medial preoptic and lateral hypothalamic areas) in both the running and food-restricted groups, compared with controls. There were no significant differences between the two experimental groups in NPY concentrations in any hypothalamic region. These findings suggest that negative energy balance, whether caused by reduced energy intake or increased expenditure, increases hypothalamic NPYergic activity. As NPY acts on the hypothalamus to increase body weight, these data support the postulated homeostatic role of NPY in maintaining nutritional state.

Beneficial effects of acarbose in the atherosclerosis-prone JCR:LA-corpulent rat.

The JCR:LA-corpulent rat is a strain exhibiting marked obesity and metabolic derangements characterized by hyperlipidemia due to hypersecretion of very-low-density lipoprotein (VLDL) and severe insulin resistance. The corpulent male rats spontaneously develop atherosclerosis and ischemic myocardial lesions. Male corpulent rats were treated with acarbose in the presence and absence of sugar-supplemented diets. The acarbose-treated rats had lower body weights at 3 months of age with unaltered food consumption, and a similar effect was seen with a high-fructose diet. Fasting insulin concentrations were decreased significantly in acarbose-treated animals at both 3 and 9 months of age, and the rate of plasma glucose disappearance increased at 3 months of age. Acarbose treatment did not affect whole-serum triglyceride concentrations, but there were modest decreases in cholesterol levels. Sugar-supplemented diets caused no significant changes in insulin or glucose concentrations, and caused small increases in nonesterified cholesterol only. Fructose- but not sucrose-supplemented diets were associated with a significantly decreased frequency of old scarred myocardial lesions. The frequency of occurrence of such lesions was also decreased by acarbose treatment. This effect of acarbose treatment may reflect improvement in insulin and glucose metabolism in treated rats. The decrease in myocardial lesions in fructose-fed rats may be secondary to increased carbohydrate metabolism via the pathways leading from fructose to triglyceride.

Hypothalamic neuropeptide Y disturbances in the obese (cp/cp) JCR:LA corpulent rat.

Regional hypothalamic neuropeptide Y (NPY) concentrations were compared between cp/cp JCR:LA corpulent rats, which were grossly obese, hyperphagic, and hyperinsulinemic, and lean (+/+) controls. In freely fed cp/cp rats, NPY levels in the arcuate nucleus (ARC) were 31% higher than in lean rats (p less than 0.001). In lean rats, chronic food restriction significantly raised NPY levels by 22% in the ARC (p less than 0.05) and by 44% in the dorsomedial nucleus (DMH; p less than 0.05). By contrast, food-restricted cp/cp rats showed no change in the ARC, but NPY levels rose in the DMH (by 36%; p less than 0.05) and ventromedial nucleus (31%; p less than 0.05). Increased NPY levels in the ARC, the major site of hypothalamic NPY synthesis, suggests increased NPYergic activity in cp/cp rats; given the central actions of NPY, this could contribute to hyperphagia, obesity, and hyperinsulinemia in this syndrome. Abnormal NPY responses to food deprivation further suggest dysregulation of NPY in cp/cp rats.

Independence of myocardial disease in the JCR:LA-corpulent rat on plasma cholesterol concentration.

The JCR:LA-corpulent rat is one of the strains incorporating the corpulent (cp) gene. Animals homozygous for the cp gene are obese, insulin-resistant and hyperlipidemic. Corpulent males, but not females or lean rats, spontaneously develop atherosclerotic and ischemic myocardial lesions. Administration of clofibrate to corpulent male rats reduced the plasma cholesterol ester concentration by 50% to that of lean controls rats. Unesterified cholesterol was slightly raised by the treatment. The markedly raised triglyceride concentrations were lowered modestly (from 282 to 220 mg/100 ml), but significantly in young rats and more markedly (from 305 to 136 mg/100 ml) in 9-month-old chronically treated rats. Apolipoproteins A-1 and E were reduced and Apo B increased by clofibrate treatment. Fasting plasma glucose and insulin concentrations were not altered nor was there any change in the impaired glucose tolerance in clofibrate-treated rats. Myocardial lesion frequency was also not reduced by clofibrate treatment. These results are consistent with others that showed inhibition of myocardial lesion formation only when the plasma insulin levels were reduced. Thus myocardial lesion formation in this strain of rats, while probably dependent upon the presence of hypertriglyceridemia, is most critically dependent upon hyperinsulinemia.

Hypolipidemic effect of beta, beta'-tetramethyl hexadecanedioic acid (MEDICA 16) in hyperlipidemic JCR:LA-corpulent rats.

Short-term treatment of male and female obese JCR:LA-corpulent rats with beta,beta'-tetramethyl hexadecanedioic acid (MEDICA 16) resulted in a marked decrease (as much as 80%) in plasma triglyceride values, with a concomitant decrease in the highly elevated very low density lipoprotein (VLDL) levels of the corpulent rat. There were modest decreases in cholesterol levels and increases in low density lipoprotein and high density lipoprotein lipids. The concentrations of apolipoproteins C-II and C-III were decreased in both the whole-serum and the VLDL fractions. Food consumption, rate of weight gain, fasting insulin levels, and the integrated insulin response to an intravenous glucose load remained unaffected. The decrease in plasma VLDL may be accounted for by inhibition of liver long-chain fatty acid synthesis at the level of ATP citrate lyase, with a concomitant reduction of VLDL triglyceride production by the liver. This decrease in plasma VLDL production was accompanied by a twofold to threefold increase in the triglyceride and cholesterol components of the low density lipoprotein and high density lipoprotein fractions, together with a twofold to fourfold decrease in plasma apolipoprotein, indicating that activation of plasma VLDL catabolism may further account for the overall hypolipidemic effect induced by MEDICA 16. The overall hypolipidemic effect of MEDICA 16 may be expected to inhibit the spontaneous atherogenic sequelae induced in the corpulent rat by severe VLDL hyperlipidemia.

Myocardial disease and catecholamine metabolism in JCR:LA-corpulent rat.

The JCR:LA-cp rat is a strain carrying the mutant cp (corpulent) gene. Animals that are homozygous cp are hyperphagous, hyperinsulinemic, hyperlipidemic, and obese. Corpulent male rats, but not females or lean rats, develop atherosclerotic lesions and myocardial lesions. Since the myocardial lesions are apparently of ischemic origin, the noradrenergic system and vascular hyperactivity and vasospasm may play a role in the pathogenesis. To test this we have studied the brain contents of the amines norepinephrine, dopamine, and 5-hydroxtryptamine and their breakdown products and depleted the peripheral sympathetic terminals with 6-hydroxydopamine. Only 5-hydroxytryptamine and 5 hydroxyindole-3-acetic acid were present at higher concentrations in the corpulent rats with depressed levels of dopamine in very young or old lean rats. The activity of monoamine oxidase may provide an indication of nonadrenergic activity in tissue. The activity in the heart increased with age and was higher in the corpulent rats than in the lean at all ages. Activity in aorta was independent of age or genotype. Long term treatment with 6-hydroxydopamine caused marked depletion of norepinephrine in the heart with only a slight decrease in brain concentration. There were no effects on the hyperlipidemia or hyperinsulinemia that are strongly associated with vascular and myocardial disease. The myocardial lesion frequency in corpulent rats was not altered by the chemical sympathectomy. The results suggest that norepinephrine and the sympathetic nervous system are probably not involved in the generation of the myocardial lesions or metabolic abnormalities in this strain of rat.

Effects of advancing age and severe food restriction on pathological processes in the insulin resistant JCR:LA-corpulent rat.

Corpulent rats of the JCR:LA-corpulent strain spontaneously develop atherosclerotic lesions, occlusive thrombi and myocardial lesions. In addition to exhibiting a VLDL hyperlipidemia they are insulin resistant. Young male corpulent rats have significantly impaired rates of clearance of plasma glucose on an intravenous glucose tolerance test in comparison to lean rats (k = 0.94 +/- 0.69 vs 2.06 +/- 0.64 x 10(-2) min-1, p less than 0.01). Food restriction to 60% of the spontaneous intake of lean controls (12 g/day) for 10 days raised the rate of glucose clearance to that of the lean rats (k = 3.01 +/- 0.40 x 10(-2) min-1) and this was highly significant compared to the rate at three months of age (p less than 0.0005). Food restriction significantly lowered the elevated insulin levels of corpulent rats at 3 and 12 months of age. It inhibited, but did not prevent, the development of hyperplasia of the islets of Langerhans. The hypertriglyceridemia was less severe in 12 month old rats (214 +/- 52 vs 282 +/- 19 mg/100 ml while total cholesterol was increased (129 +/- 20 vs 85 +/- 5.5 mg/100 ml). Severe food restriction halved the triglyceride concentration at both 3 and 12 months of age while total cholesterol was unaffected. The food restriction throughout life up to 12 months of age, however, did inhibit the development of advanced myocardial lesions.

Prevention of myocardial lesions in JCR:LA-corpulent rats by nifedipine.

Male rats of the JCR:LA-corpulent strain spontaneously develop atherosclerosis and myocardial lesions if corpulent. The corpulent rats exhibit a marked very low density hyperlipidemia and insulin resistance. The incidence of both vascular and myocardial lesions correlates strongly with the hyperinsulinemia, but not with the hyperlipidemia. Corpulent male rats were chronically treated with nifedipine or acetylsalicylic acid to explore the roles of smooth muscle spasm and platelet activity in induction of the myocardial lesions. Acetylsalicylic acid treatment was associated with no significant changes in fasting glucose, insulin, or lipid concentrations. Nifedipine caused no significant changes in glucose concentration but was associated with mildly increased insulin levels. Treatment with nifedipine resulted in significant decreases in serum triglyceride concentrations. The decreases were confined to longer-chain triacylglycerol molecular species with no change in the concentration of molecular species with 48 or 50 acyl carbon atoms. There was no effect on myocardial lesion frequency with acetylsalicylic acid treatment. In contrast, nifedipine prevented the development of old organized scarred lesions. This effect is similar to that seen with treatments that markedly reduce the insulin resistance. These findings suggest that platelet-initiated thrombus formation is not an important factor in lesion formation in the JCR:LA-cp rat, but that smooth muscle spasm is probably important.

Plasma lipid secretion and clearance in hyperlipidemic JCR:LA-corpulent rats.

The JCR:LA-corpulent rat is an obese, hyperlipidemic, hyperinsulinemic strain that is atherosclerosis-prone and develops myocardial lesions. The hyperlipidemia is due to elevated plasma levels of a large relatively triglyceride-rich very low density lipoprotein (VLDL). Both corpulent and lean male and female rats were studied. Postheparin lipid clearance and apparent hepatic secretion rate after Triton WR1339 inhibition of lipoprotein lipase were determined. The concentrations of cholesterol and cholesteryl esters were not significantly altered by either treatment. Triglycerides showed rapid postheparin clearance in corpulent rats. The apparent hepatic secretion rate was markedly higher in corpulent male rats than in lean male rats, and the rate in corpulent females was again higher, reflecting the higher serum triglyceride concentrations in corpulent female rats. The relative secretion rate of C:48 triglyceride molecular species was lower than that of the C:50 to C:56 species, while the postheparin clearance of C:48 triglyceride molecular species was impaired compared to the C:50 species and those with higher carbon numbers. This effect was more marked in the male than in the female corpulent rats. The results indicate that VLDL hyperlipidemia in the corpulent rat is due to hepatic hypersecretion of VLDL and not to a defect in lipoprotein lipase. Further, the atherogenesis that is characteristic of the corpulent male rat may be related to the differential metabolism of fatty acids.

Reduction of hyperlipidemia in the LA/N-corpulent rat by dietary fish oil containing n-3 fatty acids.

The LA/N rat, when homozygous for the corpulent gene (cp/cp), is obese, hyperphageous, hyperinsulinemic, hypertriglyceridemic and prone to the development of vascular and myocardial lesions. The hypertriglyceridemia, which in 3-month-old cp/cp males is 282 +/- 42 mg/dl and in females, 512 +/- 83 mg/dl, results from the presence of a large triacylglycerol-rich VLDL. The moderate hypercholesterolemia in these animals is largely due to markedly elevated HDL levels, which reach 172 +/- 21 mg total lipid/dl in males and 154 +/- 22 mg total lipid/dl in females. The LA/N-cp rat is thus an interesting animal model of endogenous hypertriglyceridemia in which to examine the hypolipidemic effects of pharmacological agents and also dietary oil supplements containing the n-3 fatty acids. In this study, 1-month-old male and female cp/cp rats were fed a normal low fat laboratory chow supplemented with either 10% olive oil or 10% redfish (Sebastes marinus) oil ad libitum for a period of 2 months. The redfish oil contained 4.9 +/- 0.1% of its total fatty acids as eicosapentaenoic (20:5(n-3)) and 2.3 +/- 0.5% as docosahexaenoic acid (22:6(n-3)), the predominant fatty acids being gondoic (20:1(n-3)), 21.9 +/- 0.9% and cetoleic acid (22:1(n-11)), 21.7 +/- 1.7%, which are of dietary origin. Daily caloric intake was similar to the oil-fed versus control rats. However, the oil-fed animals weighed significantly more than the controls after 2 months of oil supplementation. Redfish oil reduced serum triacylglycerols by 54% in males and 45% in females after 2 months. VLDL levels, after the same time period, were reduced by 44% in males and 39% in females. HDL lipid mass was significantly reduced in both sexes (by 27% in males and 49% in females). However, the levels remained above those of male LA/N +/+ rats of the same age and Long-Evens rats. Olive oil feeding significantly reduced serum cholesterol, triacyglycerols and phospholipids in male but only cholesterol and phospholipids in female animals. This oil had no significant effect upon VLDL total lipid levels in either sex, but significantly increased the particle diameter with a concomitant reduction in the cholesterol and phospholipid content. HDL total lipid levels were unaffected: However, HDL total cholesterol increased significantly in males only. Both oils markedly reduced serum LDL levels in both sexes.(ABSTRACT TRUNCATED AT 400 WORDS)